MEDICAL ED NG UC UI AT A CONTINUING TIN IO CON N MEDICAL EDUCATION PUBLICATION CME

ISSUE 20 New and Emerging Approaches to Ocular Surface In ammation A

STEPHEN PFLUGFELDER, MD The immune zyme, and immunoglobu- environment of the ocular surface o ers multiple lins, which exert antimicro- opportunities for pharmaceutical intervention. bial and antiinflammatory Following the exa mple of other medical specialties, eff ects.1 Transmembrane and ophthalmologists are likely to see an in ux of more secreted mucins are released targeted therapies for ocular surface in ammation. in response to foreign, nox- ious, or antigenic stimuli. B Secreted mucins (such as Under normal circumstances, complex, tightly woven MUC5AC and MUC7) may immune mechanisms on the ocular surface keep the safe participate in defense by from invasion or insult. A certain level of transient, physi- preventing pathogen bind- ological infl ammation is a necessary part of this operation, ing or by surrounding and dominated by the elements of the innate or intrinsic immune removing contaminants.2 FIGURE 1 A. Neovascularization and system. Infl ammation becomes pathological when these same Resident immune cells like infi ltrates in a 13-year-old patient elements become dysregulated, as in autoimmune or chronic macrophages deal with ocu- with chronic recurrent infl ammatory conditions, and go from being protective to and marginal . B. Regression lar surface invasion in rela- of corneal neovascularization after 1 damaging of host ocular surface tissues. tively nonspecifi c ways, but month of topical corticosteroid. (Images Treating pathological infl ammation always carries the risk do have pattern-recognition courtesy of Dr. Pfl ugfelder.) of interrupting or disabling important physiological immune receptors (including toll- and protections, an understanding that continues to drive antiin- NOD-like receptors) that can respond to molecular patterns fl ammatory and immunomodulatory drug development ef- associated with pathogens or tissue damage.3 forts toward more specifi c targets. Key to success will be under- Once activated, pattern recognition receptors trigger signal- standing the pathways and infl ammatory mediators at play in ing pathways that lead to the production of proinfl ammatory conditions—particularly dry (DED), allergy, and, cytokines, chemokines, and proteins associated with antimi- oft en, infection—characterized by pathological infl ammation. crobial and tissue repair actions. Key mediators include tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6.1,3 In INTERSECTING IMMUNE PATHWAYS In addition to the physical barriers created by the mucin See INSIDE for: glycocalyx and the tight junctions between ocular surface Infl ammation Management and Prevention of epithelial cells, innate ocular surface immune mechanisms Corneal Graft Rejection by Pedram Hamrah, MD, FACS include secretory proteins in tears, such as lactoferrin, lyso-

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Supported byTopics an unrestricted in OCULAR educational ANTIINFLAMMATORIES grant from Shire. 1 addition to immune cells, resident ocular TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 20 surface epithelial cells participate in some STATEMENT OF NEED (JavaScript™ and Java™ enabled). For Mac® users: Mac OS® of these mechanisms and have their own The control of ocular infl ammation is a critical aspect of X 10.4 (Tiger®) or newer; Safari™ 3.0 or newer; Mozilla® pattern recognition receptors, including medical and surgical ophthalmic practice. Despite their Firefox® 2.0 or newer (JavaScript™ and Java™ enabled). Internet connection required: Cable modem, DSL, or 4,5 side eff ects, antiinfl ammatory drugs are used to treat a toll-like receptors (TLR) 3 and TLR4. very wide range of conditions throughout the eye, from better. When activated, these receptors help ocular surface disease and allergic to poste- rior segment conditions. Use of antiinfl ammatory agents DATE OF ORIGINAL RELEASE January 2018. Approved ramp up the immune response by releas- is also critical in ocular surgery, contributing greatly to for a period of 12 months. patient comfort and positive outcomes. ing more proinfl ammatory mediators. ACCREDITATION STATEMENT The ocular antiinfl ammatory landscape is changing as This activity has been planned and implemented in ac- Whether the inciting event is micro- research reveals more about the role of infl ammation in cordance with the accreditation requirements and poli- a range of ocular conditions and as new antiinfl ammatory bial invasion, allergen exposure, or hy- cies of the Accreditation Council for Continuing Medical agents enter the market.1,2 Twenty years ago, for example, Education (ACCME) through the joint providership of the perosmolar stress, eventually this cascade the idea of using a topical corticosteroid to treat dry eye University of Florida College of Medicine and Candeo and/or was viewed with alarm; of infl ammatory signaling can set the Clinical/Science Communications, LLC. The University of today, it is accepted practice. stage for adaptive immune mechanisms. Florida College of Medicine is accredited by the ACCME Although corticosteroids and nonsteroidal antiinfl am- to provide continuing medical education for physicians. Adaptive immune responses are matory drugs (NSAIDs) have been the mainstays of the ocular anti-infl ammatory armamentarium, a number of initiated when antigen presenting cells CREDIT DESIGNATION STATEMENT new agents with novel mechanisms of action (and new The University of Florida College of Medicine designates ocular drug delivery systems) have come to market or are this enduring material for a maximum of 1 AMA PRA (APCs), primarily dendritic cells on 3,4 being made ready for market. Category 1 Credit™. Physicians should claim only the the ocular surface, encounter a specifi c As indications expand and change, and as new drugs, credit commensurate with the extent of their participa- antigen. APCs activate eff ector T cells or formulations, and delivery systems become available, tion in the activity. clinicians require up-to-date protocols for drug selec- prime naive T cells in the regional lymph tion and use. Such protocols are also needed for routine EDITORIAL BOARD / FACULTY ADVISORS nodes. Th e T cells then migrate back to (but nevertheless off -label) uses of corticosteroids and Marguerite B. McDonald, MD, FACS, practices at NSAIDs because important diff erences in effi cacy, safety, Ophthalmic Consultants of Long Island, and is a clinical the target tissue, disable and remove in- and tolerability exist between these classes and among professor of ophthalmology at the New York University vading pathogens, and release cytokines formulations within each of these classes.5,6 School of Medicine. She is also an adjunct clinical profes- By putting the latest published evidence into the context sor of ophthalmology at Tulane University Health Sciences that can trigger further cell recruitment of current clinical practice, Topics in Ocular Antiinfl amma- Center. She is a consultant to Allergan, Alcon, Abbott and cause tissue damage.6 tories equips ophthalmologists to maintain competen- Medical Optics, Bausch + Lomb, FOCUS Laboratories, cies and narrow gaps between their actual and optimal Shire, OCuSOFT, Altaire, Bio-Tissue, BlephEx, Oculus USA, In the case of noninfectious infl am- infl ammation management practices, across the range and Optical Express. mation, numerous possible autoantigens of clinical situations in which current and novel ocular Victor L. Perez, MD, is a professor of ophthalmology at antiinfl ammatories may be used. the Duke University School of Medicine. He is also the have been identifi ed as triggers of chron- director of Duke Eye Center's Ocular Immunology Cen- ic adaptive ocular surface responses.7 REFERENCES ter and Ocular Surface Program. He has received grant/ 1. Song JS, Hyon JY, Lee D, et al. Current practice pattern research support from the National Institutes of Health, Various subsets of T helper (Th) for dry eye patients in South Korea: a multicenter study. and is a consultant for Allergan, EyeGate, and Shire. He is cells may be generated depending on Korean Journal of Ophthalmology. 2014;28(2):115-21. also a stock shareholder for EyeGate. 2. Ciulla TA, Harris A, McIntyre N, Jonescu-Cuypers C. Treat- Matthew J. Gray, MD, is an assistant professor in the patterns encountered during antigen ment of diabetic with sustained-release department of ophthalmology at the University of presentation. Th1 and Th17 cells are glucocorticoids: intravitreal triamcinolone acetonide, Florida College of Medicine. He states that in the past 12 dexamethasone implant, and fl uocinolone acetonide months, he has not had a fi nancial relationship with any proinfl ammatory and implicated in the implant. Expert Opin Pharmacother. 2014;15(7):953-9. commercial organization that produces, markets, resells, pathogenesis DED; they secrete inter- 3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies or distributes healthcare goods or services consumed by feron (IFN)-gamma and IL-17, respec- for noninfectious : what may be coming to the or used on patients relevant to this manuscript. clinics. J Ophthalmol. 2014;2014:310329. Pedram Hamrah, MD, is associate professor of ophthal- 6,8 tively. Th 1 and Th 2 cells are involved in 4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, and mology, Tufts University School of Medicine, and director the OPUS-1 Study Group. Lifi tegrast ophthalmic solu- of the Center for Translational Ocular Immunology, Tufts the allergic immune response, secreting tion 5.0% for treatment of dry eye disease: results Medical Center. Dr. Hamrah has received grant/research IL-4 and IL-5, promoting IgE synthesis, of the OPUS-1 phase 3 study. Ophthalmology. 2014 support from CooperVision, Shire, Allergan, Bausch + 1,9 Feb;121(2):475-83. Lomb, Dompé, and GlaxoSmithKline plc. He is also a and activating eosinophils. 5. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol consultant for Shire, Allergan, Bausch + Lomb, Dompé, etabonate gel 0.5% for postoperative pain and infl am- EyeGate Pharma, Noveome, Deva, Aerie Pharmaceuticals, DETECTING INFLAMMATION mation after surgery: results of a multicenter TissueTech, and ReVision Optics. trial. Clin Ophthalmol. 2012;6:1113-24. Stephen C. Pfl ugfelder, MD, is a professor, James and The inflammatory status of the 6. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt Margaret Elkins Chair, and director of the Ocular Surface in clinical practice: our experience vs a meta-analysis Center at the Cullen Eye Institute, department of ophthal- ocular surface is constantly shift ing, of the literature. Clin Exp Ophthalmol. 2012;S1:003. mology, Baylor College of Medicine, in Houston, TX. Dr. Pfl ugfelder states that he is a consultant for Allergan, Shire, due to changes in oxygenation, tear OFF-LABEL USE STATEMENT 3 and Senju and has received research support from Shire. turnover, and blink rate. At the cellu- This work may discuss off -label uses of medications. DISCLAIMER lar level, some degree of ocular surface GENERAL INFORMATION Participants have an implied responsibility to use the new- infl ammation is likely to be widespread. This CME activity is sponsored by the University of Florida ly acquired information to enhance patient outcomes and Even in the absence of frank signs of College of Medicine and is supported by an unrestricted professional development. The information presented in educational grant from Shire. this activity is not meant to serve as a guideline for patient infl ammation and tissue damage, we The University of Florida College of Medicine designates care. Procedures, medications, and other courses of diag- can assume that there are measurable this activity for a maximum of 1 AMA PRA Category 1 nosis and treatment discussed or suggested in this activity Credit™. There is no fee to participate in this activity. In should not be used by clinicians without evaluation of increases in infl ammatory mediators in order to receive CME credit, participants should read their patients’ conditions and possible contraindications the tears of most patients with mild to the report, and then take the posttest. A score of 80% or dangers in use, applicable manufacturer’s product 10 is required to qualify for CME credit. Estimated time to information, and comparison with recommendations of moderate DED symptoms. It is likely complete the activity is 60 minutes. On completion, take other authorities. the test online at http://cme.ufl .edu/ed/self-study/toai/ that a large proportion of contact COMMERCIAL SUPPORTERS System requirements for this activity are: For PC us- wearers, even those who are tolerating ers: Windows® 2000, XP, 2003 Server, or Vista; Internet This activity is supported by an unrestricted educational lens wear well, have low but above- Explorer® 6.0 or newer, or Mozilla® Firefox® 2.0 or newer grant from Shire.

2 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ normal ocular surface infl ammation.11,12 To optimally manage infl ammatory conditions of the CORE CONCEPTS ocular surface, there is a need for more validated biomarkers ✦ Activation of adaptive, T cell-mediated immunity is a 13 of disease and for better point-of-care tests. While not a direct hallmark of pathological ocular surface infl ammation. measure of infl ammation, tear osmolarity testing is a reason- ✦ The consequences of mild-to-moderate infl ammation able surrogate, as hyperosmolarity is recognized as a driver 13 might be primarily symptomatic, but chronic, persistent of infl ammation, tissue damage, and symptoms in DED. A infl ammation can do lasting tissue damage. point-of-care test for matrix metalloproteinase-9 (MMP-9) level is useful to confi rm the presence of infl ammation on the ✦ Corticosteroids are a mainstay of ocular surface infl ammation management, but their broad activity surface of the eye, but not its etiology. MMP-9, an enzyme in- comes with the potential for serious side eff ects. volved in tissue remodeling, is elevated in many infl ammatory conditions, including DED, allergy, and very likely, infection.13 ✦ Following the examples of other medical specialties, drug development in this area is expected to focus on specifi c molecular targets. INDICATIONS FOR TREATMENT Left untreated, mild-to-moderate ocular surface infl am- ✦ Current best practices for managing ocular surface mation may have largely symptomatic consequences. In the infl ammation include, where possible, treating early to cases of mild DED and allergy, at least at this point, we do minimize tissue damage and using targeted therapies. not have strong evidence to suggest that tissue damage has occurred. But over time, moderate-to-severe ocular surface acute fl are-ups of allergic conjunctivitis, DED, or blepharitis, or infl ammation can induce cellular changes and even tissue the sequelae of ocular surface infection (Figure 1A and B). But remodeling. Loss of epithelial and goblet cells can lead to con- in certain cases, with appropriate monitoring, some of these junctival scarring. Meibomian glands can become infl amed, lower-potency steroids are used longer-term to manage ocular keratinized, and atrophy, and the whole lid margin can be- surface infl ammation. Corticosteroids with higher potency and come vascularized or irregular. Corneal neovascularization, better penetration into the anterior chamber (eg, loteprednol marginal infi ltrates, or recurrent erosions can lead to scarring etabonate suspension or gel 0.5%, prednisolone acetate 1%, dif- and consequent vision changes. luprednate emulsion 0.05%, or dexamethasone) may be reserved Th ere is broad consensus among eyecare practitioners that for postoperative and intraocular infl ammation control.16 infl ammation should ideally be addressed before such changes Some degree of infl ammation is essential to the healing occur, but it may be diffi cult to determine the cutoff point in of an infectious process, but a severe infl ammatory response individual cases (ie, is a given patient’s chronic mild infl am- can produce lasting damage. However, infl ammation control mation likely to progress to the point of damage?). In general, for ocular surface infection can be tricky. Th e management the recognition that ocular surface infl ammation can be pro- of infl ammation in cases of infectious keratitis, particularly gressive has lowered many clinicians’ threshold for treatment. with corticosteroids, should be undertaken cautiously, always with adequate antimicrobial coverage in place, and never in CONTROLLING INFLAMMATION: CORTICOSTEROIDS cases of active fungal, herpetic, or Acanthamoeba infection.17 We have an increasing number of agents approved to treat Th e pain and infl ammation of most cases of infectious ocular surface infl ammation, in addition to off -label options. conjunctivitis are managed with supportive measures, but Th e most powerful and broad-acting are the topical corticoste- emerging research into the use of a combination povidone roids. Corticosteroids exert an antiinfl ammatory eff ect primari- iodine/dexamethasone formulation for the treatment of viral ly by binding to glucocorticoid receptors in cells. Once activated, conjunctivitis is promising, showing more rapid clinical and these receptors inhibit infl ammation via direct and indirect ge- microbial resolution versus placebo or povidone iodine alone.18 nomic eff ects and via non-genomic pathways (including through membrane-associated receptors).14 Th ese numerous signaling ALLERGY AND DED pathways account for both the broad antiinfl ammatory effi cacy Some of the newer ophthalmic anti-allergy drugs, particu- of corticosteroids and their potential for side eff ects, particu- larly the dual-acting antihistamine/mast-cell stabilizing agents larly with long-term use.14,15 In the eye, these include increased (including olopatadine solution 0.1% or 0.2%, bepotastine intraocular pressure, , and opportunistic infections. besilate solution 1.5%, and alcaft adine solution 0.25%), are We are fortunate to have a range of topical ophthalmic very useful at controlling the allergic/infl ammatory process corticosteroids available, including those that are relatively on the ocular surface. Th ese agents act at multiple points on low in potency, such as fl uorometholone suspension 0.1% or the allergic/infl ammatory cascade, blocking the H1 histamine loteprednol etabonate suspension 0.2%.15,16 Th ese are suitable receptor, preventing mast-cell degranulation, and inhibiting for ocular surface infl ammatory conditions, including allergic eosinophils, leukotrienes, and cytokines.9 conjunctivitis, for which the 0.2% concentration of loteprednol For DED, in addition to corticosteroids, we have cyclospo- has a specifi c indication. rine emulsion 0.05% and lifi tegrast ophthalmic solution 5%. In general, due to the potential for serious side eff ects, topi- Cyclosporine inhibits the IL-2 activation of T lymphocytes, cal corticosteroids are best used in short pulses, to help control and can reduce infl ammatory markers and normalize osmo-

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 3 larity in DED.19 Cyclosporine has also been shown through POTENTIAL TARGETS research and clinical experience to be useful for improving An example of a targeted antiinfl ammatory therapy mov- goblet cell density and reducing epithelial cell apoptosis, ing into ophthalmology is adalimumab, a biologic TNF-α making it particularly appropriate for aqueous defi cient and/ blocker originally brought to market for the treatment of rheu- or Sjogren disease-mediated DED.19 matoid arthritis, which now adds uveitis to its growing list of Lifi tegrast was FDA-approved in 2016 for DED and has approved indications.25 Other systemic anti-TNF-α drugs have also been studied in allergic conjunctivitis.20 Lifi tegrast is a also been tested in mouse models of DED, with mixed results, small-molecule integrin antagonist, believed to work by block- though a topically administered solution of infl iximab showed ing the interaction between intercellular adhesion molecule increased tear volume and goblet cell density and decreased 1 (ICAM-1) and lymphocyte function-associated antigen 1 levels of infl ammatory cytokines in a mouse model of DED.19 (LFA-1), which in turn inhibits T cell migration and recruit- Tofacitinib, a janus kinase (JAK) inhibitor also indicated ment and the release of infl ammatory cytokines.8,19 Lifi tegrast for rheumatoid arthritis, was studied clinically in an oph- seems to have a more rapid onset of symptom improvement thalmic formulation for DED. Th ough it was found to be well than cyclosporine, which can take months to reduce irritation tolerated with effi cacy comparable to cyclosporine, it did not symptoms; lifi tegrast might be a worthwhile choice where more achieve its primary effi cacy endpoint and was not developed rapid symptom improvement is a priority.21 With cyclosporine, further.26,27 Th e continued need for reliable DED biomarkers some clinicians advocate induction therapy with a corticoste- has long challenged the design of DED treatment trials, which roid such as loteprednol etabonate to hasten symptom relief.22 may have been the source of tofacitinib’s apparent failure.13,27 Oral supplementation with essential fatty acids is oft en A topical interleukin-1 (IL-1) receptor inhibitor (isuna- used in conjunction with other DED treatments with the aim of kinra) showed initial promise for the treatment of allergic reducing ocular surface infl ammation and improving meibum conjunctivitis but failed to meet its primary endpoint in a composition. Several clinical studies evaluating the use of ome- phase 3 clinical trial; it has also been studied in early-phase ga-3 and/or omega-6 fatty acid supplementation have shown clinical trials for DED.28,29 improvements in dry eye symptoms and measures such as tear IFN-γ is another important infl ammatory cytokine and fi lm breakup time, osmolarity, and infl ammatory markers; but potential drug target for DED. Several DED therapies, includ- more large-scale, randomized, controlled studies are needed ing cyclosporine and lifi tegrast, have been shown to block in order to establish optimum treatment recommendations.19 IFN-γ in vitro as a consequence of their primary actions.8,19 Antibodies against IFN-γ have shown potential in mouse TREATMENT GAPS models of DED and in systemic autoimmune diseases.6 Th e “holy grail” of infl ammation control, on the ocular Other pipeline antiinfl ammatory therapies include novel surface and throughout the body, would be something with delivery mechanisms or formulations that enhance ocular the antiinfl ammatory potency of a corticosteroid minus the surface residence time or cellular penetration. A preparation undesirable side eff ects. A number of selective glucocorticoid of loteprednol etabonate using mucous-penetrating nanopar- receptor agonists and modifiers (so-called SEGRAs and ticles is currently being investigated in phase 3 clinical trials, SGRMs) have been under investigation in recent years. One, for the treatment of post-cataract surgery pain and infl amma- mapracorat, showed promising preclinical and early-stage tion, and, separately, for the short-term treatment of DED.30 results in a topical ophthalmic formulation and was studied for the treatment of allergic conjunctivitis, DED, and post- WHERE POSSIBLE, AIM FOR EARLY, TARGETED TREATMENT cataract infl ammation and pain; but its development has been Th ere is a growing clinical consensus that infl ammation abandoned.23 Th ough the possibility is no doubt exciting, the should be addressed early, both to improve patient quality of challenge of developing agents that induce some, but not all, life and to prevent the consequences of chronic infl ammation. of the eff ects of glucocorticoid receptor activation points to At this point in time, that probably means taking a multi- the staggering complexity of steroid signaling.14,23 pronged approach, using one or more strategies to achieve that Following the example of other specialties, such as rheu- eff ect. Acute fl ares of ocular surface infl ammation can most matology, gastroenterology, or dermatology, it is reasonable oft en be managed eff ectively with corticosteroids, with a num- to expect an infl ux of antiinfl ammatory therapies that target ber of adjunctive options that are suitable for long-term use. particular cytokines or inhibit a specifi c T-cell signaling pathway. Lifi tegrast is the fi rst FDA-approved example of an Stephen C. Pfl ugfelder, MD, is a professor, James and Margaret Elkins Chair, integrin antagonist in ophthalmology, but other ophthalmic and director of the Ocular Surface Center at the Cullen Eye Institute, department drugs that work along integrin signaling pathways are being of ophthalmology, Baylor College of Medicine, in Houston, TX. Dr. Pfl ugfelder investigated. Ideally, highly targeted therapies will mean fewer states that he is a consultant for Allergan, Shire, and Senju and has received unwanted adverse eff ects on immune function, though of research support from Shire. Medical writer Jennifer Zweibel of Candeo Clinical/ course, such eff ects would remain a potential concern. Using Science Communications, LLC, assisted in the preparation of this manuscript. the examples of cyclosporine and lifi tegrast, however, we have learned that targeting T cells on the ocular surface does not seem to predispose patients to opportunistic infection.22,24 PFLUGFELDER REFERENCES begin on page 9

4 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ In ammation Management and Prevention of Corneal Graft Rejection

PEDRAM HAMRAH, MD, FACS In ammation CORE CONCEPTS contributes signi cantly to the increased risk of corneal ✦ Infl ammation, neovascularization, and previous rejection transplant rejection. Managing in ammation suppress- are important risk factors for corneal graft rejection. es antigen delivery, angiogenesis, and lymphangiogen- ✦ Rejection can involve any tissue layer of the graft, and esis, resulting in an improved rate of long-term graft more than one type can occur in the same patient. survival. Current standards for managing in ammation ✦ For low-risk patients, topical corticosteroids are usually and graft rejection include topical and systemic cortico- suffi cient to suppress infl ammation and rejection. steroids and immunosuppressive drugs. ✦ Corticosteroids can be combined with immunosuppressants in high-risk cases or where there are Th e is an immune-privileged site, in which the signs of rejection. infl ammatory immune response to foreign antigens is gen- ✦ Emerging therapies target neovascularization to erally limited. Immune privilege is mediated by multiple combat the host immune response, and bioengineered mechanisms: physical barriers prevent the entry and exit of alternatives to corneal grafts are being investigated. cells and large molecules; immunosuppressive factors inhibit immune cell activation; and immune tolerance to antigens can arise via anterior chamber-associated immune deviation.1,2 in children is challenging and requires specialized surgical Corneal transplants are usually performed without sys- techniques. Rejection occurs faster and more frequently in temic immunosuppression, a practice implemented for other children than in adults and is oft en irreversible, so postop- solid tissue transplants to minimize rejection.3 Th e short-term erative management requires close monitoring and specifi c survival expected for corneal transplants is higher than for protocols for managing infl ammation.13 other organs, with a 90% fi rst-year survival rate for uncom- Size and position matter in terms of risk of graft rejection, plicated, low-risk graft s,4 dropping to 55% aft er 15 years.5 A with larger and more eccentric graft s posing a higher threat comparison of graft survival rates over three 10-year periods of rejection, potentially due to the closer proximity of donor indicates that there has been no signifi cant improvement antigens to the recipient’s limbal vasculature, and thus, their in long-term corneal graft survival over 30 years, despite access to the immune system.11 In addition, full thickness improvements in surgical techniques.6 Advances in systemic penetrating keratoplasties have a greater risk of rejection than immunosuppression have resulted in improvements in long- partial thickness transplants. Th e 2-year survival rate for a term survival of other solid tissue transplants and the overall low-risk, full thickness penetrating keratoplasty is about 80%, survival rate of corneal graft s over 15 years is no better than whereas studies have indicated that partial corneal transplants, other solid tissue transplants.7 For high-risk corneal graft s, such as endothelial keratoplasty, have low rejections rates of survival aft er 5 years is less than 35% without immunosup- 10% for DSAEK and 5% for DMEK.14 However, the chances pression, which is lower than for other tissue transplants.5,8 of success for a patient undergoing a partial transplant are also aff ected by other factors, including previous episodes of RISK FACTORS rejection or ocular infl ammation. Neovascularization of the cornea signifi cantly raises the risk of graft rejection. In particular, deep stromal vasculariza- MECHANISM OF CORNEAL GRAFT REJECTION tion of more than two quadrants in the cornea is considered to Immune privilege may be compromised by infl ammation be a high-risk.9,10 Likewise, a previous graft rejection classifi es and neovascularization. Th e normal cornea lacks blood and a patient as high-risk. A history of graft rejection predisposes lymphatic vessels, and contains immature antigen presenting the patient to an immune response, and each subsequent graft cells (APCs) in the central cornea.15 Infl ammation or trauma is associated with a reduced likelihood of success.9 Infl amma- can induce both angiogenesis and lymphangiogenesis, and tion, infection, past injuries, ocular surgery, and ocular surface the newly formed blood and lymphatic vessels subsequently diseases are also contributing factors.10,11 A history of keratitis facilitate the migration of immune cells into the cornea and due to herpes simplex virus (HSV) increases the risk of graft the egress of APC from the cornea to draining lymph nodes. rejection.10 Studies in a mouse model indicate that this is due Graft rejection is induced by activation of either host or to persistent infl ammation and vascularization, as well as an donor APCs in the cornea, and infl ammatory signals promote anti-HSV adaptive immune response.12 the migration of APCs into the corneal stroma. Donor antigens Age is a risk factor because of the more vigorous immune can be presented to naïve T cells directly by donor APCs, or response that occurs in younger patients.13 Corneal graft ing captured and transported by host APCs to the lymph nodes

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 5 TABLE I Ongoing and completed clinical trials of anti-VEGF treatments for corneal neovascularization DRUG IDENTIFIER TITLE STAGE REFERENCE Bevacizumab NCT00559936 Topical Avastin for treatment of corneal neovascularization Completed [Dastjerdi 2009] [Cheng 2012] Bevacizumab NCT00512876 Eff ectiveness and safety of topical bevacizumab (Avastin) for Completed treatment of corneal neovascularization Bevacizumab NCT01072357 Safety and effi cacy of bevacizumab in high-risk corneal Completed transplant survival Bevacizumab NCT01996826 A multi-center study of the safety and effi cacy of bevacizumab in Recruiting high-risk corneal transplant survival Pazopanib NCT01257750 Treatment of corneal neovascularization with topical pazopanib Completed [Amparo 2013] Ranibizumab NCT00681889 Eff ectiveness and safety of topical ranibizumab for treatment of Completed corneal neovascularization Ranibizumab NCT00769145 Ranibizumab for the inhibition of neovascularization in the Completed cornea following corneal transplant surgery Source: www.clinicaltrials.gov Dastjerdi MH, Al-Arfaj KM, Nallasamy N, et al. Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol. 2009;127(4):381-9. Cheng SF, Dastjerdi MH, Ferrari G, et al. Short-term topical bevacizumab in the treatment of stable corneal neovascularization. Am J Ophthalmol. 2012;154(6):940-8.e1. Amparo F, Sadrai Z, Jin Y, et al. Safety and effi cacy of the multitargeted receptor kinase inhibitor pazopanib in the treatment of corneal neovascularization. Invest Ophthalmol Vis Sci. 2013;54(1):537-44. via lymphatic vessels, where they are presented to the host im- epithelium and the stroma. mune system and presented to cytotoxic T cells and T helper 3. Stromal rejection features stromal edema and scarring, and cells. Sensitized T cells expand, are recruited to the eye and occurs close to sites of neovascularization in the stroma. mount an attack on the endothelial cells or other cells in the 4. Endothelial rejection, the most common form, is revealed cornea, resulting in tissue rejection.8,9 by corneal edema and an endothelial rejection line, the Khodadoust line, that moves from the periphery to the RECOGNIZING GRAFT REJECTION center of the graft . Diff erentiating between infection and rejection can be dif- fi cult, as may overlap. However, it is criti- MINIMIZING RISK cally important because corticosteroids, a mainstay of graft Prior to performing corneal transplant surgery, it is advis- rejection management, are contraindicated during an active able to ensure that infl ammation is absent and the ocular sur- infection, such as with . Examination by slit- face is healthy.10 Corticosteroids remain the fi rst-line therapy lamp biomicroscopy might not be suffi cient for diagnosis, and for managing infl ammation during and aft er surgery.17 During techniques such as in vivo confocal microscopy can help to de- surgery, intravenous corticosteroids such as methylpredniso- tect fungal elements or Acanthamoeba cysts and trophozoites, lone can be used to suppress infl ammation, and pulsed IV and thus potentially guide the correct course of treatment.16 methylprednisolone (125-500mg) and dexamethasone (100mg Clinical experience shows that rejection is rarely seen or 1mg per kg body weight) are both eff ective in treating acute within the fi rst month in patients who have not previously rejection episodes.5,8,18 undergone a . However, patients with Wherever possible, lamellar or partial thickness kerato- previous transplant rejections are already sensitized to donor plasty is preferable to full-thickness keratoplasty, because of antigens and rejection can become apparent sooner. the decreased risk of rejection and failure.19 For a patient with Typical symptoms that suggest graft rejection are redness, anterior stromal scarring, for example, performing anterior photosensitivity, decreasing vision, pain, and the sensation lamellar keratoplasty preserves the patient’s own endothelium, of ocular pressure. Cell and fl are in the anterior chamber is thus removing the possibility of endothelial rejection and also indicative of rejection. Other signs depend on the layer increasing the overall chance of graft survival. of tissue in which rejection is occurring. For patients with a history of HSV infection, the use of Rejection can aff ect any layer of the transplanted tissue, oral antivirals such as acyclovir combined with immunosup- and more than one type of rejection may occur at the same pression with cyclosporine A brings graft survival up to a rate time. Corneal graft rejection can be classifi ed into four types, comparable to that of low-risk graft s.10 based on aff ected layer:11 1. Epithelial rejection is characterized by a raised epithelial de- MANAGING INFLAMMATION AFTER SURGERY marcation line, indicating damaged donor epithelial cells. Aft er surgery, it is critical to suppress infl ammation to 2. Subepithelial rejection is characterized by whitish sub- limit the recognition of donor antigens by the host immune epithelial infi ltrates of 0.2 mm to 0.5 mm between the system. In low-risk cases, topical corticosteroids applied daily

6 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ may be suffi cient for prophylaxis and reversing rejection, if cornea, and can be extruded, and at present, bioengineered detected early. In higher-risk situations, more aggressive anti- corneal equivalents only show potential for partial-thickness infl ammatory therapy is advisable. When there are signs of keratoplasty in which the endothelium remains intact.27 rejection, topical steroids can be applied every hour or two.11 In Although these experimental therapies hold promise for severe cases, or for noncompliant patients, intraocular steroid minimizing the possibility of rejection, further research is injections, such as intracameral, transseptal or sub-Tenon’s needed before they become fully viable alternatives to tissue triamcinolone, can be administered.20-22 graft s. At present, the chances of success can be maximized by In high-risk cases, steroids can be used postoperatively in considering the patient’s history, choosing the most appropri- combination with topical immunosuppressive therapies such ate type of graft , and minimizing post-surgical infl ammation as cyclosporine A (CsA) or tacrolimus. Although topical CsA with anti-infl ammatories and immunosuppressives through alone is probably less eff ective than steroid therapy, there is vigilant monitoring for signs and symptoms of rejection. evidence that a combination of steroids and CsA is superior to steroids alone in high-risk cases.23 In cases that do not respond Pedram Hamrah, MD, is associate professor of ophthalmology, Tufts Univer- to topical treatment, systemic tacrolimus or CsA can be used sity School of Medicine and director of the Center for Translational Ocular and may be combined with pulsed steroid injection.23,24 Where Immunology, Tufts Medical Center. Dr. Hamrah has received grant/research there is severe rejection, patients may remain on systemic im- support from CooperVision, Shire, Allergan, Bausch + Lomb, Dompé, and munosuppressive therapy for one or two years. GlaxoSmithKline plc. He is also a consultant for Shire, Allergan, Bausch + Chronic corticosteroid therapy comes with a risk of side Lomb, Dompé, EyeGate Pharma, Noveome, Deva, Aerie Pharmaceuticals, Tis- eff ects, such as increased intraocular pressure (IOP), cataract sueTech, and ReVision Optics. Medical writer David Loebel, PhD, of Markey formation, and secondary opportunistic infections. When Medical Consulting Pty Ltd, assisted in the preparation of this manuscript. patients experience elevated IOP as a response to prophylactic corticosteroid therapy, loteprednol etabonate, a corticosteroid REFERENCES 1. Hori J. Mechanisms of immune privilege in the anterior segment of the eye: with a demonstrated lower risk of IOP elevation (compared what we learn from corneal transplantation. J Ocul Biol Dis Infor. 2008;1(2- to, for example, prednisolone acetate or dexamethasone), can 4):94-100. be used as an alternative.25 2. Zhou R, Caspi RR. Ocular immune privilege. F1000 Biol Rep. 2010 18;2. pii:3. 3. Niederkorn JY. Cornea: Window to ocular immunology. Curr Immunol Rev. MONITORING PATIENTS ON LONG-TERM THERAPY 2011;7(3):328-35. Follow-up for patients on topical anti-inflammatory 4. Waldock A, Cook SD. Corneal transplantation: how successful are we? Br J Ophthalmol. 2000;84(8):813-5. therapies is advised once per month to examine for signs of 5. Abud TB, Di Zazzo A, Kheirkhah A, Dana R. Systemic immunomodulatory rejection for the fi rst year. At all follow-up visits, it is useful to strategies in high-risk corneal transplantation. J Ophthalmic Vis Res. 2017 review possible symptoms of rejection in detail with patients, 12(1):81-92. 6. Bidaut-Garnier M, Monnet E, Prongué A, et al. Evolution of corneal graft and instruct patients to call the clinic if they experience any survival over a 30-year period and comparison of surgical techniques: a cohort such symptoms. study. Am J Ophthalmol. 2016;163:59-69. For patients who are on long-term systemic immunosup- 7. Williams KA, Esterman AJ, Bartlett C, et al. How eff ective is penetrating corneal transplantation? Factors infl uencing long-term outcome in multivari- pression, some physicians may be suffi ciently familiar with the ate analysis. Transplantation. 2006;81(6):896-901. drugs and their side eff ects to be comfortable monitoring these 8. Qazi Y, Hamrah P. Corneal allograft rejection: immunopathogenesis to patients clinically and by serology. Alternatively, monitoring therapeutics. J Clin Cell Immunol. 2013 20;2013(Suppl 9). pii: 006. 26 9. Panda A, Vanathi M, Kumar A, Dash Y, Priya S. Corneal graft rejection. can be done in collaboration with the transplant surgeon. Surv Ophthalmol. 2007;52(4):375-96. 10. Jabbehdari S, Rafi i AB, Yazdanpanah G, Hamrah P, Holland EJ, Djalilian NEW AND EMERGING THERAPIES AR. Update on the management of high-risk penetrating keratoplasty. Curr Ophthalmol Rep. 2017;5(1):38-48. Drugs that target the vascular endothelial growth factor 11. Dua HS, Azuara-Blanco A. Corneal allograft rejection: risk factors, diag- (VEGF) pathway have been shown to be eff ective in treating nosis, prevention, and treatment. Indian J Ophthalmol. 1999;47(1):3-9. ocular diseases that involve neovascularization, including age- 12. Kuff ova L, Knickelbein JE, Yu T, et al. High-risk corneal graft rejection in 26 the setting of previous corneal herpes simplex virus (HSV)-1 infection. Invest related and neovascular . A Ophthalmol Vis Sci. 2016;57(4):1578-87. number of clinical trials evaluating the effi cacy of anti-VEGF 13. Di Zazzo A, Bonini S, Crugliano S, Fortunato M. Th e challenging manage- drugs in suppressing corneal angiogenesis or lymphangiogen- ment of pediatric corneal transplantation: an overview of surgical and clinical experiences. Jpn J Ophthalmol. 2017;61(3):207-17. esis have been completed or are currently recruiting (Table I). 14. Deng SX, Lee WB, Hammersmith KM, et al. Descemet membrane endo- Artifi cial hold the potential to remove the risk of thelial keratoplasty: safety and outcomes: a report by the American Academy tissue rejection altogether. Keratoprostheses, synthetically gen- of Ophthalmology. Ophthalmology. 2017. pii: S0161-6420(17)32521-6. 15. Stein-Streilein J. Mechanisms of immune privilege in the posterior eye. Int erated corneas that are not fully bio-integrated and only provide Rev Immunol. 2013;32(1):42-56. restoration of central vision, are options for patients with end- 16. Villani E, Baudouin C, Efron N, et al. In vivo confocal microscopy of the stage corneal disease and those at very high risk of graft failure.27 ocular surface: from bench to bedside. Curr Eye Res. 2014;39(3):213-31. 17. Kharod-Dholakia B, Randleman JB, Bromley JG, Stulting RD. Prevention Bioengineered, collagen-based corneal equivalents are being and treatment of corneal graft rejection: current practice patterns of the explored in animal models and clinical trials outside the United cornea society (2011). Cornea. 2015 Jun;34(6):609-14. States (NCT02277054).28 However, keratoprostheses suff er from a lack of stable integration, can result in melting of the donor HAMRAH REFERENCES continue on page 8

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 7 EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 20 This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Shire. Participants must score at least 80% on this exam in order to receive credit. The University of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. To take this exam and obtain credit, please take the test online at http://cme.ufl.edu/ed/self-study/toai/. Expires: December 31, 2018.

1. Which of the following is NOT a 5. Which of the following is a 8. Which type of rejection does a mediator and potential target for validated biomarker of ocular Khodadoust line characterize? ocular surface antiinflammatory surface inflammation? A. Epithelial drugs? A. Lipopolysaccharide B. Subepithelial A. IFN-γ B. Matrix metalloproteinase-9 C. Stromal B. TNF-α C. Immunoglobulin A D. Endothelial C. IL-1β D. Hyperosmolarity D. SGRM 9. Which type of graft is likely to have 6. Bevacizumab, ranibizumab, and the lowest risk of rejection? 2. Adalimumab is a TNF-α inhibitor pazopanib may be beneficial in A. Lamellar recently approved for: preventing rejection because they: B. Large A. Moderate-to-severe DED A. Inhibit inflammation C. Eccentric B. Vernal B. Inhibit VEGF activity and D. Full thickness C. Uveitis neovascularization C. Inhibit PDGF activity and D. Aqueous-deficient DED 10. Pathological inflammation in DED neovascularization is primarily mediated by: D. Kill cytotoxic T cells 3. In high-risk cases, or when there is A. Eosinophils severe rejection, corticosteroids can B. Th1 and Th17 cells be combined with 7. Lifitegrast works by: C. Mast cells A. Topical immunosuppressants A. Blocking LFA-1 from binding D. Basophils B. Systemic immunosuppressants ICAM-1 C. A and B B. Inhibiting IL-17 release D. None of the above C. Blocking histamine and stabilizing mast cells 4. Risk factors for graft rejection D. Promoting MMP-9 include: production A. Previous graft rejection B. Vascularized cornea C. Ocular inflammation D. All of the above

HAMRAH REFERENCES continued from page 7 18. Tandon R, Verma K, Chawla B, et al. Intravenous single transseptal depot injection. Ocul Immunol 25. Sheppard JD, Comstock TL, Cavet ME. Impact dexamethasone vs methylprednisolone pulse Inflamm. 2009;17(3):216-20. of the topical ophthalmic corticosteroid lotepre- therapy in the treatment of acute endothelial 22. Goyal S, Uwaydat SH. Multiquadrant subtenon dnol etabonate on intraocular pressure. Adv Ther. graft rejection. Eye (Lond). 2009;23(3):635-9. triamcinolone injection for acute corneal graft 2016;33:532-52. 19. Akanda ZZ, Naeem A, Russell E, et al. rejection: a case report. Case Rep Ophthalmol. 26. Chang JH, Garg NK, Lunde E, et al. Corneal Graft rejection rate and graft failure rate of 2017;8(2):308-13. neovascularization: an anti-VEGF therapy re- penetrating keratoplasty (PKP) vs lamellar 23. Abudou M, Wu T, Evans JR, Chen X. Immuno- view. Surv Ophthalmol. 2012;57(5):415-29. procedures: a systematic review. PLoS One. 2015 suppressants for the prophylaxis of corneal graft 27. Yu T, Rajendran V, Griffith M, et al. High-risk 17;10(3):e0119934. rejection after penetrating keratoplasty. Cochrane corneal allografts: A therapeutic challenge. World 20. Maris PJ Jr, Correnti AJ, Donnenfeld ED. Intra- Database Syst Rev. 2015;(8):CD007603. J Transplant. 2016;6(1):10-27. cameral triamcinolone acetonide as treatment for 24. Young AL, Rao SK, Cheng LL, et al. Combined 28. Lin Y, Zheng Q, Hua S, et al. Cross-linked decel- endothelial allograft rejection after penetrating intravenous pulse methylprednisolone and lularized porcine corneal graft for treating fungal keratoplasty. Cornea. 2008;27(7):847-50. oral cyclosporine A in the treatment of corneal keratitis. Sci Rep. 2017;7:9955. 21. Silva PS, Singh RJ, Bakri SJ, et al. Vitreous graft rejection: 5-year experience. Eye (Lond). concentration of triamcinolone acetonide after a 2002;16(3):304-8.

8 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ PFLUGFELDER continued from page 4 REFERENCES 17. Lietman TM, Sheppard JD. What is the role of steroids in treating infection? 1. Akpek EK, Gottsch JD. Immune defense at the ocular surface. Eye. Topics in Ocular Antiinflammatories. 2013;2:6-8. 2003;17:949-56. 18. Narvekar A, Pepose J, Ahuja A, Liu W, Haque R. Dexamethasone/povidone- 2. Hodges RR, Dartt DA. Tear film mucins: front line defenders of the ocular iodine ophthalmic suspension for treatment of adenoviral conjunctivitis: surface; comparison with airway and gastrointestinal tract mucins. Exp Eye results of a phase 2, randomized, controlled trial. Presented at the American Res. 2013;117:62-78. Academy of Optometry Annual Meeting; Chicago, IL; October 11-14, 2017. 3. Galletti JG, Guzman M, Giordano MN. Mucosal immune tolerance at the 19. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy ocular surface in health and disease. Immunology. 2017;150:397-407. report. Ocul Surf. 2017;15(3):575-628. 4. Pearlman E, Sun Y, Roy S, et al. Host defense at the ocular surface. Int Rev 20. Shire. Efficacy study to evaluate the effectiveness of 3 concentrations of Immunol. 2013;32(1)4-18. sar 1118 in allergic conjunctivitis https://clinicaltrials.gov/ct2/show/ 5. Erdinest N, Aviel G, Moallem E, et al. Expression and activation of toll-like NCT00882687 receptor 3 and toll-like receptor 4 on human corneal epithelial and conjunc- 21. Holland EJ, Luchs J, Karpecki PM. Lifitegrast for the treatment of dry eye tival fibroblasts.J Inflamm (Lond). 2014;11:3. disease. Ophthalmology. 2017;124:53-60. 6. Pflugfelder SC, Corrales RM, de Paiva CS. T helper cytokines in dry eye 22. Sheppard JD, Donnenfeld ED, Holland EJ, et al. Effect of loteprednol disease. Exp Eye Res. 2013;117:118-25 etabonate 0.5% on initiation of dry eye treatment with topical cyclosporine 7. Stern ME, Schaumberg CS, Dana R, Calonge M, Niederkorn JY, Pflugfelder 0.05%. Eye Contact Lens. 2014;40:289-96. SC. Autoimmunity at the ocular surface: pathogenesis and regulation. Mu- 23. Baiula M, Spampinato S. Mapracorat, a novel non-steroidal selective cosal Immunol. 2010 Sep;3(5):425-42. glucocorticoid receptor agonist for the treatment of allergic conjunctivitis. 8. Perez VL, Pflugfelder SC, Zhang S, Shojaei A, Haque R. Lifitegrast, a novel Inflammation & Allergy – Drug Targets. 2014;13:289-98. integrin antagonist for treatment of dry eye disease. Ocul Surf. 2016;14(2):207- 24. Donnenfeld ED, Karpecki PM, Majmudar PA. Safety of lifitegrast oph- 15. thalmic solution 5.0% in patients with dry eye disease: a 1-year, multicenter, 9. Mishra GP, Tamboli V, Jwala J, Mitra AK. Recent patents and emerging randomized, placebo-controlled study. Cornea. 2016;35(6):741-8. therapeutics in the treatment of allergic conjunctivitis. Recent Pat Inflamm 25. Humira [package insert]. North Chicago, IL: AbbVie Inc.; May, 2017. Allergy Drug Discov. 2011;5(1):26-36. 26. Liew SH, Nichols KK, Klamerus KJ, Li JZ, Zhang M, Foulks GN. Tofaci- 10. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and tinib (CP-690,550), a janus kinase inhibitor for dry eye disease. Ophthalmol- classification report.Ocul Surf. 2017;15(3):276-83. ogy. 2012;119(7):1328-35. 11. Pisella PJ, Malet F, Lejeune S, et al. Ocular surface changes induced by contact 27. Abelson MB, McLaughlin J. Sorting out the Stats from the Jaks. Review lens wear. Cornea. 2001;20(8):820-5. of Ophthalmology. 2013 April. https://www.reviewofophthalmology.com/ 12. Yüksel EC, İskeleli G, Talaz S, Akyol S. Comparative analysis of tear film article/sorting-out-the-stats-from-the-jaks. Accessed October 11, 2017. levels of inflammatory mediators in contact lens users.Curr Eye Res. 2016 28. Eleven Biotherapeutics. Eleven Biotherapeutics reports phase 3 data on Apr;41(4):441-7. isunakinra (EBI-005) in allergic conjunctivitis. http://www.fiercebiotech. 13. Roy NS, Wei Y, Kuklinski E, Asbell PA. The growing need for validated com/biotech/eleven-biotherapeutics-reports-phase-3-data-on-isunakinra- biomarkers and endpoints for dry eye clinical research. Invest Ophthalmol ebi-005-allergic-conjunctivitis. Accessed October 11, 2017. Vis Sci. 2017;58(Suppl):BIO1-BIO19. 29. Goldstein MH, Martel JR, Sall K, et al. Multicenter study of a novel topical 14. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new interleukin-1 receptor inhibitor, isunakinra, in subjects with moderate to mechanisms for old drugs. N Engl J Med. 2005;353:1711-23. severe dry eye disease. Eye Contact Lens. 2017 Sept;43(5):287-96. 15. Comstock TL, DeCory HH. Advances in corticosteroid therapy for ocular 30. Kala Pharmaceuticals, Inc. Kala Pharmaceuticals announces positive results inflammation: loteprednol etabonate.Int J Inflamm. 2012;Article ID 789623, from confirmatory phase 3 trial of KPI-121 1% following cataract surgery. 16. Pleyer U, Ursell PG, Rama P. Intraocular pressure effects of common topical http://kalarx.com/wp-content/uploads/docs/KPI-121%20Phase%203%20 steroids for post-cataract inflammation: are they all the same?Ophthalmol Cataract%20Surgery%20Release%205.1.17%20FINAL.pdf Accessed Oc- Ther. 2013;2:55-72. tober 11, 2017.

To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 9